1. Overview

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones involved in glucose regulation, insulin secretion, appetite, and energy balance. Medicines that activate their receptors were initially developed for type 2 diabetes mellitus and later became important therapies for obesity. Their established effects include improved glycemic control, appetite reduction, weight loss, and, for some agents, cardiovascular protection. Scientific interest has expanded beyond these metabolic indications because incretin-based therapies may also influence biological pathways involved in degeneration of the central nervous system. The main agents studied in this field include the GLP-1 receptor agonists liraglutide, semaglutide, exenatide, and lixisenatide, as well as dual GLP-1/GIP receptor agonists such as tirzepatide. Although these compounds have shown neuroprotective potential, they are not established treatments for neurodegenerative diseases.

Neurodegenerative disorders are characterized by progressive neuronal dysfunction and loss. Despite important differences among individual diseases, several mechanisms are shared, including chronic neuroinflammation, mitochondrial dysfunction, oxidative stress, impaired cellular energy metabolism, defective autophagy, and abnormal protein accumulation. Experimental studies suggest that GLP-1 receptor agonists may improve cerebral glucose utilization, preserve mitochondrial integrity, stimulate autophagy, and reduce the accumulation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein. These findings have also increased interest in the relationship between cerebral insulin resistance and neurodegeneration, particularly in Alzheimer’s disease.

2. Proposed Neuroprotective Mechanisms

One of the most important proposed actions of incretin-based therapies is the regulation of neuroinflammation. Persistent activation of microglia and astrocytes can increase the release of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and other inflammatory mediators. These responses may contribute to synaptic dysfunction, oxidative injury, tau hyperphosphorylation, beta-amyloid deposition, and progressive neuronal loss. GLP-1 receptor agonists may suppress nuclear factor kappa B signaling and NLRP3 inflammasome activation, reduce inflammatory cytokine production, limit pro-inflammatory microglial polarization, and promote more protective immune-cell responses.

These agents may also improve neuronal energy balance through insulin and growth-factor signaling, support mitochondrial biogenesis, and facilitate cellular repair. Mitochondria are essential for neuronal survival because the brain has high energy requirements. When mitochondrial function is impaired, neurons become more vulnerable to oxidative stress, inflammation, and excitotoxicity. By improving metabolic efficiency and reducing mitochondrial damage, incretin-based therapies may increase neuronal resistance to injury.

Autophagy represents another important mechanism. This cellular process removes damaged organelles and abnormal proteins. Impaired autophagy can allow beta-amyloid, tau, alpha-synuclein, or mutant huntingtin to accumulate and interfere with neuronal function. Experimental evidence indicates that GLP-1 receptor stimulation may increase autophagic activity and improve cellular clearance. The diagram on page 3 of the review integrates these effects across neurons, microglia, astrocytes, and endothelial cells, linking anti-inflammatory activity, mitochondrial protection, enhanced autophagy, and reduced pathological protein accumulation with neuronal survival.

3. Alzheimer’s Disease

Alzheimer’s disease is associated with progressive cognitive decline, beta-amyloid deposition, tau pathology, synaptic loss, neuroinflammation, and disturbances in brain energy metabolism. GLP-1 receptor agonists have therefore been studied as possible treatments capable of influencing several disease pathways simultaneously. Liraglutide produced encouraging findings in laboratory models, including reductions in amyloid-related pathology and improvements in metabolic and inflammatory processes.

Clinical results have been less conclusive. The ELAD trial was a multicenter, randomized, double-blind, placebo-controlled phase 2b study involving 204 non-diabetic participants with mild to moderate Alzheimer’s disease who were followed for 52 weeks. Its primary outcome was change in cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography. Liraglutide did not significantly improve this primary measure. Participants receiving the drug showed better performance on an executive-function assessment, but no significant improvements were observed in activities of daily living or overall dementia severity. Liraglutide was generally reported as safe and well tolerated.

The larger EVOKE and EVOKE+ phase 3 trials investigated oral semaglutide in more than 3,800 participants with early symptomatic Alzheimer’s disease and confirmed amyloid pathology. The main endpoint was change in the Clinical Dementia Rating–Sum of Boxes over 104 weeks. According to the review, semaglutide did not meaningfully slow cognitive decline or disease progression compared with placebo, and the trials were discontinued after negative clinical outcomes. These results illustrate the difficulty of translating promising laboratory mechanisms into measurable clinical benefit. Future research may need to identify responsive patient subgroups, earlier treatment windows, or more suitable biological markers.

4. Parkinson’s Disease

Parkinson’s disease involves progressive loss of dopamine-producing neurons in the substantia nigra, alpha-synuclein accumulation, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. These features provide a strong rationale for investigating incretin-based therapies. GLP-1 receptor agonists may protect dopaminergic neurons, improve mitochondrial function, reduce inflammatory signaling, and potentially limit alpha-synuclein-related pathology.

Early clinical studies produced encouraging findings. In a phase 2 trial involving 156 people with early Parkinson’s disease, lixisenatide was associated with less progression of motor symptoms after one year than placebo. However, gastrointestinal adverse effects, especially nausea and vomiting, were frequent. Exenatide also showed possible benefits in an earlier randomized study. Treated participants had an average 3.5-point advantage on the motor section of the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale after 48 weeks, and the difference persisted after a washout period. This finding raised the possibility of an effect extending beyond temporary symptom control.

The larger phase 3 Exenatide-PD3 trial did not confirm the earlier results. Once-weekly exenatide did not significantly slow disease progression or improve secondary outcomes compared with placebo. The review also described the MOST-ABLE study as an evaluation of oral semaglutide in Parkinson’s disease. Overall, the evidence remains mixed, and no incretin-based therapy has yet demonstrated a confirmed disease-modifying effect in Parkinson’s disease.

5. Other Neurodegenerative and Neuroinflammatory Disorders

Research has also examined incretin therapies in multiple system atrophy, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. Evidence in these conditions is much less developed and is derived mainly from animal or cellular studies.

In multiple system atrophy, experimental research suggests that GLP-1 receptor activation may improve insulin signaling, reduce alpha-synuclein accumulation, limit neuroinflammation, and preserve dopaminergic neurons. Limited clinical observations of weekly exenatide suggested slower worsening on a disease-rating scale, but objective secondary outcomes involving gait, imaging, and biomarkers did not show significant improvement.

Amyotrophic lateral sclerosis is characterized by progressive motor-neuron loss, glial activation, oxidative stress, and neuroinflammation. Experimental studies suggest that GLP-1 signaling may reduce neuronal apoptosis, support neuroplasticity, and improve motor-neuron survival. Robust clinical evidence, however, is not yet available.

Huntington’s disease is caused by a CAG repeat expansion in the HTT gene and involves mutant huntingtin accumulation, impaired autophagy, oxidative stress, and neuronal death. In animal models, liraglutide has improved insulin signaling, stimulated autophagy, reduced mutant huntingtin aggregation, and limited oxidative injury. Exendin-4 has also improved motor performance and survival in experimental models. These effects have not yet been confirmed in large human studies.

In experimental models of multiple sclerosis, exendin-4, liraglutide, and dulaglutide have reduced oxidative stress, suppressed microglial activation, promoted remyelination, stabilized the blood–brain barrier, and improved neurological function. Early clinical experience indicates that GLP-1 receptor agonists may be tolerated in people with multiple sclerosis and can improve metabolic outcomes without clearly worsening disease activity. Nevertheless, large randomized trials have not demonstrated benefits for relapse rates, magnetic resonance imaging findings, or long-term disability progression.

6. Dual Agonists and Emerging Therapies

Dual GLP-1/GIP receptor agonists may provide broader effects than medicines that activate only the GLP-1 receptor. Simultaneous stimulation of both pathways could improve metabolic control, suppress inflammatory responses, support mitochondrial stability, and strengthen neuronal survival mechanisms. Tirzepatide is the best-known example. A retrospective real-world cohort study cited by the review associated tirzepatide with a lower incidence of dementia than semaglutide or sodium-glucose cotransporter 2 inhibitors in adults with type 2 diabetes who did not have dementia at baseline. Because this was an observational analysis, it cannot prove that tirzepatide directly prevents dementia; differences between treatment groups and other confounding factors may have influenced the result.

GLP-2-based compounds represent another emerging direction. GLP-2 analogues are mainly used for intestinal disorders, but preclinical studies suggest possible central nervous system effects. In a mouse model of Parkinson’s disease, a GLP-2 analogue improved motor activity, preserved dopaminergic neurons, reduced alpha-synuclein accumulation, and lowered inflammatory signaling. A dual GLP-2/GIP receptor agonist produced stronger protective effects than GLP-2 alone in another experimental model. These findings remain preliminary and require validation in human trials.

7. Clinical Significance and Limitations

The main therapeutic appeal of incretin-based drugs is their ability to target metabolic dysfunction, inflammation, mitochondrial impairment, and abnormal protein handling at the same time. This approach may be particularly relevant to patients who have both cardiometabolic disease and neurological disorders. However, biological plausibility does not guarantee clinical effectiveness. Negative phase 3 findings in Alzheimer’s and Parkinson’s diseases demonstrate that benefits observed in cell cultures, animals, observational cohorts, or small trials may not persist in larger controlled studies.

Major research questions include whether some agents reach the brain more effectively than others, whether treatment must begin before extensive neuronal loss occurs, whether metabolic status influences response, and whether dual or multi-receptor agonists are more effective than single-receptor therapies. Studies also need reliable biomarkers capable of distinguishing temporary symptomatic effects from true modification of disease progression. Safety and tolerability remain important, particularly because gastrointestinal adverse effects can limit adherence.

8. Conclusion

GLP-1 and GIP receptor agonists are established metabolic therapies with potential neuroprotective properties. Experimental research suggests that they may reduce neuroinflammation, improve mitochondrial and neuronal energy function, enhance autophagy, regulate insulin-related signaling, and limit the accumulation of disease-associated proteins. Clinical evidence is strongest but inconsistent in Alzheimer’s and Parkinson’s diseases. In multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, and multiple system atrophy, most findings remain preclinical.

Dual GLP-1/GIP agonists and GLP-2-based compounds are promising research directions, but further controlled clinical trials are required to determine whether these therapies can prevent, slow, or modify neurodegenerative disease. At present, they should be regarded as investigational neurological treatments rather than established components of neurodegenerative disease management.